Intestinal parasitic roundworms, most notably hookworms, whipworms, and Ascaris, infect over 2 billion people in tropical countries-more than 1.5X the populations of North American and Europe combined. These parasites are the leading cause of disease burden in school-aged children worldwide, with infections leading to anemia, malnutrition, growth stunting, cognitive and learning defects, school absenteeism, and reduced future earns. These parasites also exact a heavy toll on pregnant women and on adults by weakening their bodies and immune systems. Few treatment options exist. All have incomplete efficacy, and concerns about parasite resistance are mounting. New anti-roundworm drugs are urgently needed. We have pioneered the development of Bacillus thuringiensis (Bt) Cry proteins that kill roundworms. Bt is natural soil bacterium harmless to humans but lethal to insects. We proved it is lethal to roundworms as well. The work here shows that the Bt protein Cry5B can cure an intestinal roundworm infection in a small mammal 3X better than the current leading drug. The research proposed is designed to optimize the therapeutic potential of Cry5B by formulating it to protect it against the mammalian digestive tract, by developing new means of purifying it, and by studying its combinatorial characteristics with known anti- roundworm drugs. Tests of Cry5B's effectiveness alone and in drug combinations will be performed using the free-living roundworm C. elegans, the mouse parasite H. bakeri, and close models of all three human parasite classes. Basic research detailing the genetic and transcriptional interaction between Cry5B and roundworms will be undertaken as well. The ultimate objective of this work is to develop an anti-roundworm drug or drug combination that is order(s) of magnitude better than any currently out there and that is highly recalcitrant to parasite resistance. PUBLIC HEALTH RELEVANCE: Intestinal parasitic roundworms infect ~2 billion people, placing a tremendous health burden on the poorest peoples and trapping them in poverty. Current drugs are incompletely effective, and there are growing concerns the parasites are becoming resistant to them. Here we propose to develop a new drug we discovered that is made by a natural soil bacterium (which is harmless to humans) and that appears to be a very potent anti-roundworm compound with activity greater than any currently available.